13-polycarbon alkyl-18,19-dinorpregn-4-en-3-ones



United States Patent Oifice 3,488,364 Patented Jan. 6, 1970 ABSTRACT OF THE DISCLOSURE The compounds of the class of 13-polycarbon alkyl- 18,19-dinorpregn-4-en-3-ones useful as androgen antagonists and progestational agents.

BACKGROUND OF THE INVENTION This invention relates to the field of new physiologically active 13 polycarbon alkyl 17,20 dihydroxy- 18,19-dinorpregn-4-en-3-one and l3-polycarbon alky1-17- hydroxy 18,19 dinorpregn-4-en-3,20-dione compounds, novel processes for their production and new intermediates useful in the preparation thereof.

The prior art compounds, l7,20-dihydroxypregn-4-en- 3-one, described by P. N. Rao et al in J. Org. Chem. 26, p. 2552 (1961) and A. L. Nussbaum et al in J. Org. Chem. 27, p. 2 (1962) have not been shown to possess anti-androgenic activity.

SUMMARY OF THE INVENTION More particularly, this invention relates to 19-norcompounds of the Formula I:

wherein R is an alkyl group having from 2 to 8 carbon atoms; R is hydrogen; R is hydroxy, or together R and R is oxo(=O); and R is hydrogen or acyl.

Among the suitable acyls may be mentioned the acyl radical of a hydroxycarbon carboxylic acid of less than 12 carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric, hexanoic and enanthic acid), the lower alkenoic acids, the cycloalkane carboxylic acids, the monocyclic aromatic carboxylic acids (e.g., benzoic acid), and the monocyclic aryl lower .alkanoic acids (e.g., phenylacetic and fl-phenylpropionic acid).

The final products of this invention are physiologically active substances which are useful as progestational agents and androgenic antagonists.

The compounds may be formulated for such administration, the concentration :and/or dosage being based on the activity of the particular compound and the requirements of the patient.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The 19-nor compounds of this invention may be prepared according to the process of the invention which may be represented by the following reaction scheme wherein R, R R and R are as hereinbefore defined:

W R I III CH3 -O-C-CHs -o-( i-oH3 CH3 0 (i=0 R R OH 20 /\i i g I I CH0 CH0 R OH if CH0 CH0 a v1 3 VIa CH3 (L/O nbmon R "OH R ----on q/ CHO I CHO I I 3 k/ VII 3 VIIa VIIIa VIII According to a feature of this invention, the 17 3-acetyll3 polycarbon alkyl 3 methoxygona-l,3,5()-triene compound (II) is converted by a known process to the corresponding 3 methoXy-1,3,5 10),17(20)-tetraen-20- acetate (III). Such process consists in reacting the 20- ketone steroids (11) with an acylating agent such as acetic anhydride, in the presence of a strongly acidic catalyst such as p-toluene sulfonic acid, sulfuric acid or perchloric acid.

The compounds of Formula H are known compounds which may be prepared by any conventional method, such as described in copending application, Ser. No. 534,353 of G. A. Hughes et al., filed Mar. 15, 1966.

The 3 methoxy-1,3,5 (10),17(20)-tetraen-20-acetate compounds (III) are then treated with an oxidizing agent, such as m-chloroperbenzoic acid, in an inert organic solvent to yield the novel 1,3,5 (10)-trien-20-acetoxy-1701,20- epoxy compounds of Formula IV.

Treatment of the 1,3,5(10)-trien-20-acetoxy-l7u,20- epoxy compounds (IV) with a base, such as dilute sodium hydroxide, yields the corresponding 1,3,5(10)-triene- 17-hydroxy-20-keto compounds of Formula V.

Reduction of the 1,3,5(10)-triene-17-hydroxy-20-keto compounds of Formula V with sodium borohydride yields the corresponding 1,3,5(10)-triene-17,20-dihydroxy compound of Formula VI which when further reduced in liquid ammonia with lithium yields the corresponding 2,5 (10)-diene-17,20-dihydroxy compound of Formula VII.

Treatment of the 2,5(10)-diene-17,20-dihydroxy compounds (VII) with concentrated hydrochloric acid yields the novel 3-keto-4-ene-17,20-dihydroxy compound of Formula I, which are novel final products of this invention.

In accordance with another feature of this invention, the 1,3,5 (10)-triene-17-hydroxy-20-keto compounds (V) are reacted with ethylene glycol to yield the corresponding 1,3,5(10) triene-17-hydroxy-20-cycloethylenedioxy compounds (V'Ia) which are reduced liquid ammonia with lithium to yield the corresponding 2,5 (10)-diene-17- hydroxy-20-cycloethylenedioxy compounds (VIIa) Treatment of the 2,5-(10)-diene-17-hydroxy-20-cycloethylene-dioxy compound (VIIa) with concentrated hydrochloric acid yield the novel 4-ene-17-hydroxy-3,20- diketo compounds (VIIIa), which are additional final products of the invention.

If desired, the 4-ene-17-hydroxy-3,20-diketo compounds may he acylated by any conventional method, such as by treatment with an acid anhydride or an acyl chloride, to form the corresponding 4-ene-17-acyloxy-3,20-diketo compounds (lXa) which are additional final products of this invention.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 13 ethyl 3 methoxy-18,19-dinOrpregna-1,3,5(10),17

A solution of 100 gm. of 17 3-acetyl-13-ethyl-3-methoxygona-1,3,5 10)-triene and 0.53 gm. of p-toluenesulfonic acid in 100 ml. of acetic anhydride is slowly distilled through a short Vigreux column at atmospheric pressure over a 4 hour period leaving approximately 30 ml. of brown residue. The residue is cooled in an ice bath, 100

IXa

ml. of water is added and the mixture is stirred for 15 minutes. The mixture is then extracted with ether and the ether extracts washed with 10% aqueous sodium hydroxide, saturated aqueous sodium bicarbonate, water, dried over anhydrous magnesium sulfate and the solvent is evaporated in vacuo yields a brown gum. Column chromatography of the gum on 60 gm. of Florisil using hexane as eluant gives, after recrystallization from methanol, 350 mg. of colorless solid which, on recrystallization from methanol, yields 13-ethyl-3-methoxy-l8,19-dinorpregna-1,3,5(10),17(20)-tetraen-20-ol, acetate having a melting point of 89-923;

REE; 5.71, 5.88 14 (weak); 284 mu (e=1,660)

Analysis.-Calcd. 01 C24H3203: C, H, 8-75. Found: C, 78.22; 'H, 8.63.

EXAMPLE 2 13 propyl 3-methoxy-1-8,19-dinorpregna-l,3,5(10),17 (20)-tetraen-20-ol, acetate Following the procedure of Example 1 but substituting 17 ,B-acet yl-1 3-propyl-3-methoxygona- 1,3,5 10) -triene for 17fl-acety1- 13-ethyl-3 methox5'g0na-1,3,5 l0) triene there is obtained 13-propyl-3-methoxy-18,19-dinorpregna- 1,3,5 10),l7 (20) -tetraen-20-ol, acetate.

EXAMPLE 3 13 butyl 3 methoxy-1 8,19-dinorpregna-1,3,5(10),17 (20)-tetraen-20-ol, acetate Following the procedure of Example 1 but substituting 17/8 -acetyl 1 13-butyl-3-methoxygona-1,3,5(10)-triene for 17 8 acetyl 13 ethyl 3 methoxygona 1,3,5(l0)- triene here is obtained 13-buty1-3-methoxy-18,19-dinorpregna-1,3,5(10),17(20)-tetraen-20-ol, acetate.

EXAMPLE 4 13 isobutyl 3-methoxy-18,19-dinorpregna-1,3,5(l0), 17(210)-tetraen-20-ol, acetate Following the procedure of Example 1, but substituting 17 B acetyl 13-isobutyl-3-methoxygona-1,3,5(10) -triene for acetyl-13-ethyl-3-methoxygona-1,3,5 (10)-triene there is obtained 13 isobutyl 3 methoxy 18,19 dinorpregna-1,3,5(10),17(20)-tetraen-20-ol, acetate.

EXAMPLE 5 20g-acetoxy-17a,20-epoxy-13-ethyl-3-methoxy-18,l9-

dinorpregna-1,3,5(10)-triene A solution of 0.95 gm. of m-chloroperbenzoic acid in 9.0 ml. of benzene is added to a solution of 1.00 gm. of 13 ethyl 3 methoxy 18,19 dinorpregna 1,3,5(10) tetraen-ZO-ol, acetate in 9.0 ml. of benzene over 5 minutes at room temperature with stirring. After stirring 20 minutes at room temperature, turbidity appeared and after 3 hours, ether is added and the solution is washed with cold 5% aqueous sodium hydroxide, saturated aqueous sodium bicarbonate, water, dried over anhydrous magnesium sulfate and then the solvent is evaporated in vacuo giving a gum which crystallized on triturating with hexane. Recrystallization from isopropanol yields 0.55 gm. of 205 acetoxy 17a,20 epoxy 13 ethyl 3 methoxg 18,19 dinorpregua 1,3,5(10) triene, M.P. 113- 12 EtOH EE; 5.71; A512? 282 (6 2,190);

Analysis.Calcd. for C H O C, 74.97; H, 8.39

Found: C, 74.91; H, 8.29.

EXAMPLE 6 20-acetoxy-17u,20epoxy-13-propyl-3-methoxy- 18 19-dinorpregna- 1,3,5 1 0) -trien-20-one Following the procedure of Example 5, but substituting 13-propyl 3-methoxy 18,l9-dinorpregna-l,3,5(10),17 (20)-tetraen 20-01, acetate for 13-ethyl S-methoxy- 18,19-dinorpregna 1,3,5(10),17(20)-tetraen 2001, ac-

etate there is obtained ZOE-acetoxy 170:,205-6POXY-13- propyl 3-methoxy 18,19-dinorpregna 1,3,5()-trien- 20-one.

EXAMPLE 7 ZOE-acetoxy-17a,205-epoxy-13-butyl-3-methoxy-18,19- dinorpregna-1,3,5(10)-trien-20-one Following the procedure of Example 5, but substituting l3-butyl-3-methoxy-18,19-dinorpregna-1,3,5(10), 17(20)-tetran 20-01, acetate for13-ethyl 3-methoxy- 18,19-dinorpregna 1,3,5(10),17(20)-tetraen 20-ol, acetate there is obtained 20g-acetoxy 17a,20-epoxy 13- butvl 3 methoxy 18,19-dinorpregna 1,3,5(10)-trien- 20-one.

EXAMPLE 8 ZOg-acetoxy-17a,20-epoxy-13-isobutyl-3-methoxyl8, 19-dinorpregna- 1,3 ,5 10 -trien-20-one Following the procedure of Example 5 but substituting 13-isobutyl 3-methoxy 18,19-dinorpregna 1,3,5(10), 17(20)-tetraen 20-01, acetate for 13-ethyl 3-methoxy- 18,19-dinorpregna 1,3,5(10),17(20)-tetraen 20-01, acetate there is obtained 205-acetoxy 17a,20.-epoxy 13- isobutyl 3-methoxy 18,19-dinorpregna-1,3,5(10)-trien- 20-one.

- EXAMPLE 9 13-ethyl-3-methoxy-18,19-dinorpregna-,3,5( 10) -trien- 17a-ol-20-one A 0.40 g. quantity of 20-acetoxy 17a,20-epoxy-13- ethyl 3-methoxy 18,19-dinorpregna 1,3,5(10*)-triene is allowed to stand at ambient temperature with 0.48 gm. of sodium hydroxide in a mixture of 60 ml. of ethanol and 20' ml. of water for 3 /2 hours. The mixture is diluted with ether, washed with saturated aqueous sodium bicarbonate, Water, dried over anhydrous magnesium sulfate and the solvent is evaporated in vacuo giving a colorless solid. Recrystallization from absolute ethanol yields 0.26 g. of 13-methyl-3-methoxy-18,19-dinorpre'gna 1,3,5(10) trien 17oz ol-20-one, MP. 164- 167,

m 2.96, 5.92m 281 m (6 2,140)

Analysis.Calcd. for C H O C, 77.15; H, 8.83. Found: C, 76.91; H, 8.65.

EXAMPLE 10 13propyl-3methoxy-18,19-dinorpregna-1,3,5(10)- trien-17a-ol-20-one Following the procedure of Example 9, but substituting 205 acetoxy 17a,20 epoxy 13 7 propyl 3 methoxy- 18,19-dinorpregna 1,3-5(10) triene for 20.5-acetoxy- 17a,20g-epoxy 13-ethyl S-methoxy 18,19-dinorpregna- 1,3,5(10)-triene there is obtained 13-propyl-3-methoxy- 18,19-dinorpregna 1,3,5(10) triene for 205 acetoxy- EXAMPLE 11 13-butyl-3-rnethoxy-18,19-dinorpregna-1,3,5(10)- trien-17a-ol-20-one KB: EtOH A A max.

Following the procedure of Example 9, but substituting ZOE-acetoxy 17a,205-epoxy 13-butyl 3-methoxy-18,19- dinorpregna 1,3,5(10)-triene for 20-acetoxy-17u,20gepoxy 13-ethyl-3-rnethoxy 18,19-dinorpregna-1,3,5(10)- triene there is obtained 13-butyl 3-methoxy 18,19- dinorpregna-1,3,5(10)-trien-17a-ol-20-one.

EXAMPLE 12 13-isobutyl-3-methoxy-18,19-dinorpregna-1,3 ,5 l0) tn'en-17a-ol-20 -one Following the procedure of Example 9, but substituting 205-acetoxy 17a,20-epoxy 13-isobutyl 3-methoxy- 18,19 dinorpregna 1,3,5(10)-triene for 2OE-acetoxy- 17a,20-epoxy 13-ethyl 3-methoxy-18,19-dinorpregna- 1,3,5 (10)-triene there is obtained 13-isobutyl-3-methoxy- 18,19-dinorpregna 1,3,5(10)-trien 17a-ol-20-one.

EXAMPLE 13 13 -ethyl-17a,20-dihydroxy-3-methoxy-18,19-dinorpregna-1,3,5 10) -trien A solution of 5.40 gm. of 13-ethyl 3-methoxy-18,19- dinorpregna 1,3,5(10)-trien 17u-ol-20-one, gm. of sodium borohydride and 500 m1. of absolute ethanol is stirred at room temperature for 14 hours. Excess glacial acetic acid is added, benzene is added and the solution is washed with water, saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and the solvent is evaporated in vacuo to yield 7.0 gm. of 13-ethyl 17a,20-dihydroxy 3-methoxy-18,19-din0rpregna 1,3,5(10)-trien.

EXAMPLE 14 13-propyl-17a,20-dihydroxy-3-methoxy-18,19-dinorpregna-1,3,5(10)-trien Following the procedure of Example 13, but substituting 13-propyl 3-methoxy 18,19 dinorpregna- 1,3,5(10)-trien 17a-ol-20-one for 13-ethyl 3-methoxy- 18,19 dinorpregna 1,3,5(10)-trien l7a-ol-20-one there is obtained 13-propyl-17a,20-dihydroxy-3-methoxy- 18,19-dinorpregna 1,3,5(10)-trien.

EXAMPLE 15 13-butyl-17a,20-dihydroxy-3-methoxy-18,19-dinorpregna- 1,3,5 10 -trien Following the procedure of Example 13, but substituting 13-butyl-3-methoxy-18,19-dinorpregna-1,3,5(10)-trien- 17aol-20-one for 13-ethyl-3-methoxy-18,19-dinorpregna- 1,3,5(10)-trien-17-a-ol-20-one there is obtained 13-butyl- 1711,20 dihydroxy 3 methoxy-18,19-dinorpregna-1,3, 5(10)-trien.

EXAMPLE 16 13-isobutyl-17a,20-dihydroxy-3-methoxy-18,19-dinorpregna-1,3,5(l0)-trien Following the procedure of Example 13, but substituting 13 isobutyl 3 methoxy 18,19-dinorpregna-1,3,5 (10)-trien-17a-ol-20-one for 13-ethyl-3-methoxy-,18,19- dinorpregna 1,3,5(10) trien-17a-ol-2-one there is 0btained 13-isobutyl 17o,20 dihydroxy-3-methoxy-18,19- dinorpregna-1,3,5(10)-trien.

EXAMPLE l7 13-ethyl-17a,20'-dihydroxy-3methoxy-l8,19- dinorpregna-2,5( 10) -diene A solution of 5.4 gm. of 13-ethyl 17a,20-dihydroxy- 3-methoxy 18,19-dinorpregna 1,3,5(10)-triene in 100 ml. of distilled tetrahydrofuran is added to 700 m1. of distilled liquid ammonia over 3 minutes giving a suspension. Immediately 5.0 gm. of lithium is added in small pieces as rapidly as possible. The blue mixture is stirred for 2 hours and 150 ml. of absolute ethanol is added over 30 minutes to discharge the blue color. Addition of warm water and the filtering of the resulting precipitate yield 4.45 gm. of 13-ethyl 17a,20-dihydroxy- 3-methoxy 18,19 dinorpregna 2,5(10)-diene, M.P. 155.

EXAMPLE 18 13-propyl-17a,20-dihydroxy-3-methoxy-18,19- dinorpregna-2,5 (10)-dien Following the procedure of Example 17, but substituting 13 propyl 17a,20 dihydroxy 3 methoxy 18, 19 dinorpregna 1,3,5(10) triene for 13 ethyl 17a, 20 dihydroxy 3 methoxy 18,19 dinorpregna 1,3,5 (10)-triene there is obtained 13-propyl-17u,20-dihydroxy- 3-meth0xy-18,l9-dinorpregna-2,5(10)-diene.

7 EXAMPLE 19 13 -butyl- 17 a,20-dihydroxy-3-methoxy-l 8 ,19-

dinorpregna-2,5(10)-diene Following the procedure of Example 17, but substi- 5 tuting 13 butyl 170;,20 dihydroxy 3 methoxy 18, 19 dinorpregna 1,3,5() triene for 13 ethyl 170;, 20 dihydroxy 3 methoxy 18,19 dinorpregna 1,3,5 (10) triene there is obtained 13-butyl-17a,20-dihydroxy- 3-methoxy-l8,l9-dinorpregna-2,5(10)-diene.

EXAMPLE 20 1 3 -isobutyl-1 7a,20-dihydroxy-3-methoxy- 1 8, l9- dinorpregna-2,5(10)-diene Following the procedure of Example 17, but substituting 13 isobutyl 1711,20 dihydroxy 3 methoxy 18, 19 dinonpregna 1,3,5(10) triene for 13 ethyl 17a, 20 dihydroxy 3 methoxy 18,19 dinorpregna 1,3,5 (10)-triene there is obtained 13-isobutyl-l7a,20-dihydroxy- 3 methoxy-18, 19-dinorpregna-2,5(10)-diene.

,7 EXAMPLE 21 13-ethyl-l7a,20-dihydroxy-18,19-dinorpregn-4-en-3-one A solution consisting of 4.20 gm. of 13-ethyl-17a,20- dihydroxy 3 methoxy 18,19 dinorpregna 2,5(10)- diene, in 117 ml. of methanol, 7.8 ml. of concentrated hydrochloric acid and 5.2 ml. of water is stirred under nitrogen for 1 hour .at room temperature. Filtering yielded 0.31 g. of. colorless solid, M.P. 158-168. The filtrate is diluted with benzene, washed with saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and the solvent is evaporated in vacuo giving 3.50 g. of a gum. The gum is columned on Grade HI Woelm neutral alumina .and eluted with benzene containing increasing-proportions of ether and recrystallization from methanol to yield 0.44 gm. of 13-ethyl-17a,20-dihydroxy- 18,l9-dinorpregna-4-en-3-one, M.P. 150-152";

AER, 2.98, 6.20 A222? 244 m (6 16,500) I Analysis.-Calcd. for C H O C, 75.86; H, 9.70. Found: C, 75130; H, 10.10.

Further elution of the colurrm with increasing proportions of ether and recrystallization from methanol and from isopropanol yielded 0.19 gm. of the corresponding ZO-epimer, M.P. 181-185";

x533; 3.00, 6.02, 6.23;; A212? 243 mu (6 15,500)

Analysis.-Calcd. for C H O C, 75.86; H, 9.70. Found: C, 75.68; H, 9.27.

EXAMPLE 22 13-propyl-17a,20-dihydroxy-18,19-dinorpregn-4-en-3-one Following the procedure of Example 21, but substituting 13 propyl 170:,20 dihydroxy 3 methoxy 18, 19 dinorpregna 2,5(10) diene for 13 ethyl l7oc,20'- dihydroxy 3 methoxy 18,19 dinorpregna 2,5(10 diene there is obtained 13-propyl-17u,20-dihydroxy-18, 19-dinorpregn-4-en-3-one.

EXAMPLE 23 13 -buty1-l7a,20-dihydroxy- 1 8, 1 9-dinorpregn-4-en-3 -one Following the procedure of Example 21, but substituting 13 butyl 1711,20 dihydroxy 3 methoxy 18, 19 dinorpregna 2,5(10) diene for 13 ethyl 1711,20- dihydroxy 3 methoxy 18,19 dinorpregna 2,5(10)- diene there is obtained 13-butyl-17a,20-dilhydroxy-18,19- dinou-pregn-4-en-3-one.

EXAMPLE 24 13 -isobutyl- 1 70:,20E-dihYd1'OXY-l 8,19-dinorpregn-4-en- 3-one Following the procedure of Example 21, but substituting 13 isobutyl 17 on,20 dihydroxy 3 methoxy 18, 19 dinorpregna 2,5(10) diene for 13 ethyl 17a,20- dihydroxy 3 methoxy 18,19 dinorpregna 2,5(10)- 8 diene there is obtained 13-isobutyl-l7a,20-dihydroxy-l8, 19-dinorpregn-4-en-3-one.

EXAMPLE 25 1 3 -ethyl-3-methoxy-20-cycloethylenedioxy- 1 8,19- dinorpregna-1,3,5 (10)-trien- 1711-01 A solution of 1.0 gm. of 13-ethyl-3-methoxy-18,19- dinonpregna 1,3,5(10) trien 17a ol 20 one in 30 m1. of ethylene glycol'and 300 ml. of benzene is refluxed 18 hours using a Dean-Stark water take ofi. The ethylene glycol layer is separated and the benzene layer is washed with saturated aqueous sodium bicarbonate, water and evaporated in vacuo. The solid residue is recrystallized from hexane to yield 0.85 gm. of 13-ethyl-3-meth0xy- 20 cycloethylenedioxy 18,19 dinorpregna 1,3,5(10)- trien-17a-ol having .a melting point of -99" C.; A 2.86, 9.25, 9.64;/..

Analysis.Calcd. for C H O C, 74.57; H, 8.87. Found: C, 74.39; H, 9.09.

EXAMPLE 26 l3-pu'op yl-3 -methoxy-20-cycloethylenedioxy-1 8, 19- dinorpregna1,3,5(10)-trien-17a-ol Following the -procedure of Example 25, but substituting 13 propyl 3 methoxy 18,19 dinorpregna 1, 3,5(10) trien 17a o1 20 one for 13 ethyl 3- methoxy 18,19 .dinorpregna 1,3,5(10) trien 17a ol- 20-one, there is obtained 13-propyl-3-methoxy-20-cycloethylenedioxy-18,19-dinorplregna-1,3,5(10)-trien-17a-ol.

. 1 EXAMPLE 27 1 3 -butyl-3 -methoxy20-cycloethylenedioxy- 1 8, l9- dinorpregna-1,3,5(10)-trien-17a-ol 1 3 -is obutyl-3 -methoxy-20-cycloethylenedioxyl 8, 19- dinorpregna'l,3,5 (10)-trien-17a-ol Following the procedure of Example 25, but substituting 13 isobutyl 3 methoxy 18,19 dinorpregna- 1,3,5(10) trien 17oz ol 20 one for 13 ethyl 3- methoxy 18,19 dinorpregna 1,3,5(10) trien 17oz ol- 20-0ne there is obtained 13-isobutyl-3-methoxy-20-cycloethylenedioxy-18,19-dinorpregna-l,3,5(10)-trien-17a-ol.

EXAMPLE 29 13-ethy1-17w-hydroxy-18,l9-dinorpregn-4-en-3,20-dione A solution of 1.0 gm. of 13-ethy1-3-methoxy-20 cycloethylenedioxy 18,19 dinorpregna 1,3,5(10) trien- 17a-ol in distilled tetrahydrofuran ml.) is .added to 250 ml. of distilled liquid ammonia over a 10 minute period. Immediately, 0.90' gm. of lithium in small pieces is added as rapidly as possible with stirring. Vigorous stirring of the blue solution is continued for 2 hours. Absolute ethanol is then added dropwise to discharge the blue color. Hot water is added and the mixture is extracted with ether. The organic extracts are washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate and the solvent is evaporated in vacuo to yield 1.10 gm. of 13 ethyl 3 methoxy 20 cycloethylenedioxy- 18,19 dinorpregna 2,5(10) diene 17a 01, 71 5.89, 5.99 1. I

1.0 gm. of the resulting product is heated at 60 in a mixture of 40 ml. of methanol, 22.5 ml. of water and 7.5 ml. of concentrated hydrochloric acid for 20 minutes. The mixture is cooled to room temperature, diluted with ether, washed with water, saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and the solvent is evaporated in vacuo. The resulting solid residue is recrystallized from ethyl acetate/ hexane to yield 0.45 gm. of 13-ethyl-17a-hydroxy-1-8,19-diuorpregn-4-en- 3,20-dione M.P. 204-206".

EXAMPLE 30 13-propyl-17a-hydroxy-18,19-dinorpregn-4-en-3,20-dione Following the procedure of Example 29, but substituting 13 propyl 3 methoxy 20 cycloethylenedioxy 18,19 dinorpregn 1,3,5() trien 17a 01 for 13 ethyl 3 methoxy cycloethylenedioxy 18,19- dinorpregn-1,3,5(10)-trien-17a-ol there is obtained 13- propyl-17a-hydroxy-18,19-dinorpregn-4-en-,3,20-dione.

EXAMPLE 3 1 13-butyl-17a-hydroxy-18,19-dinorpregn-4-en-3 ,20-dione Following the procedure of Example 29, but substituting 13 butyl 3 methoxy 20 cycloethylenedioxy- 18,19 dinorpregna 1,3,5(10) trien 17a 01 for 13- ethyl 3 methoxy 20 cycloethylenedioxy 18,19 dinorpregna-1,3,5(10)-trien-17a-ol there is obtained 13- butyl-17a-hydroxy-18,19-dinorpregn-4-en-3,20-dione.

EXAMPLE 32 13-isobutyl-175t-hydroxy-18,19-dinorpregn-4-en-3,20 dione Following the procedure of Example 29, but substituting 13 isobutyl 3 methoxy 20 cycloethylenedioxy- 18,19-dinorpregna-1,3,5(10)-trien-17a-ol for 13-ethyl-3- methoxy 20 cycloethylenedioxy 18,19 dinorpregna- 1,3,5(10)-trien-17a-ol there is obtained 13-lSObl1ty1-170thydroxy-18,19-dinorpregn-4-en-3,20-dione.

EXAMPLE 33 13-ethyl-17u-hydroxy-18,19-dinorpregn-4-en-3,20-dione, 17-acetate To a solution of 0.50 gm. of 13-ethyl-17a-hydroxy- 18,19-dinorpregn-4-en-3,20-dione in 4.0 ml. of acetyl chloride is added 8.0 ml. of acetic anhydride then 0.40 ml. of pyridine dropwise with rapid stirring. The slurry is warmed to achieve complete solution, then cooled to room temperature and stirred at room temperature for 65 hours. The solvents are evaporated in vacuo giving a yellow solid residue. The crude product is dissolved in 10.0 ml. of tetrahydrofuran and 10.0 ml. of methanol and then 10.0 ml. of methanolic potassium hydroxide is added at 0 C. under nitrogen. Stirring under nitrogen at 0 C. is continued for 1 hour. The mixture is poured into aqueous sodium bicarbonate, diluted with ether, the organic layer washed with water, dried over anhydrous so dium sulfate and the solvent is evaporated in vacuo. The residue crystallized on trituration with ether. Rapid column chromatography on neutral alumina with 100% benzene and recrystallization from hexane/ethyl acetate yields 0.205 gm. of 13-ethyl-17a-hydroxy-18,19-dinorpregn-4-en-3,20-dione, 17-acetate; M.P. 186189;

m, 5.77, 5.83, 5.99, 6.205; mg? 239 m, (6 16,100)

Analysis.Calcd. for C H O C, 74.16; H, 8.66. Found: C, 74.25; H, 8.66.

10 EXAMPLE 34 13-propyl-17a-hydroxy-18,19-dinorpregn-4-en-3,20-dione, 17-acetate Following the procedure of Example 33, but substituting 13 propyl 17a hydroxy 18,19 dinorpregn 4- en-3,20-dione for 13-ethyl-17whydroxy-18,19-dinorpregn 4-en-3,20-dione, there is obtained 13-propy1-17a-hydroxy- 18, l9-dinorpregn-4-en-3-20-dione, 17-acetate.

EXAMPLE 35 13-butyl-17a-hydroxy-18, l9-dinopregn-4-en-3,20-dione, 17-acetate Following the procedure of Example 33, but substituting 13 butyl 17a hydroxy 18,19 dinorpregn-4-en- 3,20-dione for 13-ethyl-17a-hydroxy-18,19-dinorpregn-4- en-3,20-dione for 13-ethyl-17 -hydroxy-18,19-dinorpregn- 18,19-dinorpregn-4-en-3,20-dione, 17-acetate.

EXAMPLE 3 6 13-isobutyl-17a-hydroxy-18,19-dinorpregn-4-en-3 ,20- dione, 17-acetate R ---OH wherein R is as hereinbefore defined.

2. A compound according to claim 1 that is 13-ethyl- 17a,20a-dihydroxy-18,19-dinorpregn-4-en-3-one.

3. A compound according to claim 1 that is 13-ethyl- 17a,20a-dihydroxy-18,19-dinorpregn-4-en-3-one.

References Cited UNITED STATES PATENTS 3/ 1968 Fried 2 60397.4 4/1968 Patchett et al 260239.55

ELBERT L. ROBERTS, Primary Examiner U.S. Cl. X.R.

33 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 88,364 Dated January 6, 1970 Daniel M. Teller, George H. Douglas and Herchel Smit It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Claim 3 should read:

3. A compound according to claim 1 that is l3-ethyl- 17a, 20P-dihydroxy-l8 l9-dinorpregn-4-ew-3-one SPGNED AND SEALED JUN 2 3 1970 wmxm E. sum. as. Atwsting Officer Commissioner of Patents 

